Pharmacological Inhibition of Endogenous Hydrogen Sulfide Production Slows Bladder Cancer Progression in an Intravesical Murine Model.

Present bladder cancer therapies have relatively limited therapeutic impact and account for one of the highest lifetime treatment costs per patient. Therefore, there is an urgent need to explore novel and optimized treatment strategies. The present study investigated the effects of inhibiting endogenous hydrogen sulfide (H2S) production on bladder cell viability and in vivo tumor progression. We targeted the H2S-producing enzyme, cystathionine γ-lyase, in 5637 cells using propargylglycine (H2S inhibitor) and performed cytofluorimetric analysis to evaluate cell viability. We then tested the efficacy of propargylglycine alone or in combination with gemcitabine (conventional chemotherapy) in an intravesical murine model of bladder cancer. Magnetic resonance imaging and immunohistochemical staining for cell proliferation, apoptosis, immune-cell infiltration, and neovascularization were performed to evaluate tumor response. Compared to control conditions or cohorts, propargylglycine administration significantly attenuated bladder cancer cell viability in vitro (p < 0.0001) and tumor growth (p < 0.002) and invasion in vivo. Furthermore, propargylglycine enhanced the anti-cancer effects of gemcitabine, resulting in tumor regression (p < 0.0001). Moreover, propargylglycine induced cleaved PARP-1-activated apoptosis (p < 0.05), as well as intratumoral CD8+ T cell (p < 0.05) and F4/80+ macrophage (p < 0.002) infiltration. Propargylglycine also reduced intratumoral neovascularization (p < 0.0001) and cell proliferation (p < 0.0002). Importantly, the pro-apoptotic and anti-neovascularization effects of gemcitabine were enhanced by propargylglycine co-administration. Our findings suggest that inhibition of endogenous H2S production can be protective against bladder cancer by enhancing the chemotherapeutic action of gemcitabine and may be a novel pharmacological target and approach for improved bladder cancer diagnosis and treatments in the future.

Effect of Sodium Thiosulfate Pre-Treatment on Renal Ischemia-Reperfusion Injury in Kidney Transplantation.

We recently reported in a rat model of kidney transplantation that the addition of sodium thiosulfate (STS) to organ preservation solution improved renal graft quality and prolonged recipient survival. The present study investigates whether STS pre-treatment would produce a similar effect. In vitro, rat kidney epithelial cells were treated with 150 µM STS before and/or during exposure to hypoxia followed by reoxygenation. In vivo, donor rats were treated with PBS or 2.4 mg/kg STS 30 min before donor kidneys were procured and stored in UW or UW+150 µM STS solution at 4 °C for 24 h. Renal grafts were then transplanted into bilaterally nephrectomised recipient rats which were then sacrificed on post-operative day 3. STS pre-treatment significantly reduced cell death compared to untreated and other treated cells in vitro (p < 0.05), which corresponded with our in vivo result (p < 0.05). However, no significant differences were observed in other parameters of tissue injury. Our results suggest that STS pre-treatment may improve renal graft function after transplantation.

Evaluating the Effects of Kidney Preservation at 10 °C with Hemopure and Sodium Thiosulfate in a Rat Model of Syngeneic Orthotopic Kidney Transplantation.

Kidney transplantation is preferred for end-stage renal disease. The current gold standard for kidney preservation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal graft damage through ischemia-reperfusion injury (IRI). We previously reported renal graft protection after SCS with a hydrogen sulfide donor, sodium thiosulfate (STS), at 4 °C. Therefore, this study aims to investigate whether SCS at 10 °C with STS and Hemopure (blood substitute), will provide similar protection. Using in vitro model of IRI, we subjected rat renal proximal tubular epithelial cells to hypoxia-reoxygenation for 24 h at 10 °C with or without STS and measured cell viability. In vivo, we preserved 36 donor kidneys of Lewis rats for 24 h in a preservation solution at 10 °C supplemented with STS, Hemopure, or both followed by transplantation. Tissue damage and recipient graft function parameters, including serum creatinine, blood urea nitrogen, urine osmolality, and glomerular filtration rate (GFR), were evaluated. STS-treated proximal tubular epithelial cells exhibited enhanced viability at 10 °C compared with untreated control cells (p < 0.05). Also, STS and Hemopure improved renal graft function compared with control grafts (p < 0.05) in the early time period after the transplant, but long-term function did not reach significance. Overall, renal graft preservation at 10 °C with STS and Hemopure supplementation has the potential to enhance graft function and reduce kidney damage, suggesting a novel approach to reducing IRI and post-transplant complications.

It seems impractical to pay people to become healthier.

Four readers panellists were asked if financial incentives would motivate people to adopt healthy behaviours (reflections May 2).